Fibrosis, the formation of excessive amounts of fibrotic or scar tissue, is a common pathologic problem in medicine. Scar tissue occludes arteries, immobilizes joints and damages internal organs, wreaking havoc on the body's ability to maintain vital functions. Every year, about 1.3 million people are hospitalized due to the damaging effects of organ fibrosis, yet doctors have few specific therapeutics to mollifies, let alone control the progressive onslaught of this condition. As a result, they often see patients disabled or killed by failing organs, circulatory insufficiency, or immobile joints infiltrated with ever increasing fibrosis and scar.
Fibrosis can follow surgery in the form of adhesions, keloid tumors, or hypertrophic (very severe) scarring. Fibrosis causes contractures and joint dislocation following severe burns, wounds, or orthopaedic injuries; it can occur in any organ is the sequelae to many disease states, such as hepatitis (liver cirrhosis), hypertension (heart failure), tuberculosis (pulmonary fibrosis), scleroderma (fibrotic skin and internal organs), diabetes (nephropathy), and atherosclerosis (fibrotic blood vessels).
Ironically, the very process designed to repair the body (ie, deposition of scar) can lead to dangerous complications. Like epoxy, scar tissue serves only a structural role. It fills in the gaps, but cannot contribute to the function of the organ in which it appears. For example, as fibrotic scar tissue replaces heart muscle damaged by hypertension, the heart becomes less elastic and thus less able to do its job. Similarly, pulmonary fibrosis causes the lungs to stiffen and decrease in size, a condition that can become life-threatening when oxygen uptake is impeded by fibrosis. Fibrotic growth can also proliferate and invade the healthy tissue that surrounds it even after the original injury heals. Too much scar tissue thus causes physiological roadblocks that disable, cripple, or kill.
In most cases, fibrosis is a reactive process, and several different factors can apparently modulate the pathways leading to tissue fibrosis. Such factors include the early inflammatory responses, local increase in fibroblast cell populations, modulation of the synthetic function of fibroblasts, and altered regulation of the biosynthesis and degradation of collagen.
One treatment approach, therefore, has been to target the early inflammatory response. Treatment with topical or systemic corticosteroids has achieved limited success, if used early in fibrosis. However, steroid therapy has little or no effect once scar tissue has already been deposited. Furthermore, prolonged administration of hydrocortisone, in pulmonary fibrotic disease for example, may actually worsen the condition, and at the same time cause cataracts and osteoporosis.
The second approach involves slowing the proliferation of those cells responsible for the increased collagen synthesis. Generally, this involves fibroblast cells, except in the vasculature where smooth muscle cells are responsible for collagen deposition. Compounds that have been used to inhibit fibroblast proliferation include benzoic hydrazide, as taught by U.S. Pat. No. 5,376,660. Benzoic hydrazide has been shown to suppress collagen synthesis and fibroblast proliferation, at least in tissue culture cells. U.S. Pat. No. 5,358,959 teaches the use of imidazole derivatives to inhibit the growth of fibroblasts by blocking the calcium-activated potassium channel. This particular agent also inhibits the proliferation of endothelial cells and vascular smooth muscle cells.
Likewise, a number of agents which affect smooth muscle cell proliferation have been tested. These compositions have included heparin, coumarin, aspirin, fish oils, calcium antagonists, steroids, prostacyclin, rapamycin, dipyridamole, ultraviolet irradiation, gamma (.gamma.)-interferon, serotonin inhibitors, methotrexate and mycophenolic acid, either alone or in various combinations.
The final treatment strategy involves directly influencing the metabolism of collagen and the other components of fibrotic tissue. Thus, drugs that interfere with the biosynthesis, accumulation and catabolism of collagen have been used in the treatment of fibrosis. Many drugs are used to inhibit collagen synthesis, including derivatives of pyridone, alkadiene, benzoquinone, pyridine, oxalylamino acid and proline analogs. However, all of these drugs suffer from the drawback of also inhibiting the normal, and required synthesis of collagen as they antagonize the detrimental synthesis that occurs during fibrosis.
One of the most important pathologies for which fibrosis is a contributing factor is cardiovascular disease. Cardiovascular disease is the leading cause of death in the Western world. In the US it accounted for 930,000 deaths in 1990. There are an estimated 1.5 million heart attacks per year in the US that result in more than 500,000 deaths annually.
One consequence of heart disease is activation of the body's renin-angiotensin-aldosterone system (RAAS). The RAAS system maintains normal fluid volume in the body. The sympathetic nervous system provokes the release of the renin from the kidneys. The release of renin is stimulated by decreased extracellular fluid volume, low renal perfusion, and decreased sodium content in the macula densa. Renin is a proteolytic enzyme that acts on angiotensinogen to produce the decapeptide angiotensin I. Angiotensin I is then converted to the octapeptide angiotensin II (AII) by the action of angiotensin-converting enzyme (ACE). All is a potent pressor agent producing a rapid elevation in blood pressure.
All also is a growth factor and plays a role in proliferation of smooth muscle cells.
We have now discovered that compounds which inhibit ACE can be used in conjunction with compounds which inhibit one or more matrix metalloproteinase (MMP) enzymes to achieve surprisingly good results in treating fibrosis and related cardiovascular diseases like ventricular dilation and heart failure.